Circadian rhythm disruption and retinal dysfunction: a bidirectional link in Alzheimer's disease?

Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer's disease. A predominant function of the retina is circadian synchronization, carrying information to the brain through the retinohypothalamic tract, which projects to the suprachiasmatic nucleus. Notably, Alzheimer's disease hallmarks, including amyloid-β, are present in the retinas of Alzheimer's disease patients, followed/associated by structural and functional disturbances.

Altered Clock Gene Expression in Female APP/PS1 Mice and Aquaporin-Dependent Amyloid Accumulation in the Retina.

Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-β (Aβ) accumulation that can directly interfere with the regulation of the circadian cycle.

Disturbed circadian rhythm and retinal degeneration in a mouse model of Alzheimer's disease.

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known.

Choroid Plexus Aquaporins in CSF Homeostasis and the Glymphatic System: Their Relevance for Alzheimer's Disease.

The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer's disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently the brain interstitium, supported by aquaporins (AQPs).

Differentially Aquaporin 5 Expression in Submandibular Glands and Cerebral Cortex in Alzheimer's Disease.

Impaired brain clearance mechanisms may result in the accumulation of aberrant proteins that define Alzheimer's disease (AD). The water channel protein astrocytic aquaporin 4 (AQP4) is essential for brain amyloid-β clearance, but it is known to be abnormally expressed in AD brains. The expression of AQPs is differentially regulated during diverse brain injuries, but, whereas AQP4 expression and function have been studied in AD, less is known about AQP5.

Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis.

Background: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis.

Results: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 healthy controls was measured by Southern blot, and we found shorter age-standardized TL in SSc patients compared to healthy controls. TL was shorter in SSc patients with ILD compared to those without ILD and in anti-topoisomerase I positive compared to anti-centromere positive patients.

TFAM-deficient mouse skin fibroblasts - an ex vivo model of mitochondrial dysfunction.

Mitochondrial dysfunction associates with several pathological processes and contributes to chronic inflammatory and ageing-related diseases. Mitochondrial transcription factor A (TFAM) plays a critical role in maintaining mtDNA integrity and function. Taking advantage of Tfamfl/fl UBC-Cre/ERT2+/+ mice to investigate mitochondrial dysfunction in the stromal cell component, we describe an inducible in vitro model of mitochondrial dysfunction by stable depletion of TFAM in primary mouse skin fibroblasts (SK-FBs) after 4-hydroxytamoxifen (4-OHT) administration.

Therapies Targeting Trained Immune Cells in Inflammatory and Autoimmune Diseases.

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming.

IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms.

Introduction: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF.

Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype.

Background: Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF).

Results: The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors.

The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages.

GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene leads to functionally defective A-MØ and the onset of pulmonary alveolar proteinosis. , macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities.

Methotrexate limits inflammation through an A20-dependent cross-tolerance mechanism.

Objectives: Methotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis (RA), but the mechanism of its anti-inflammatory action is not fully understood. In RA, macrophages display a proinflammatory polarisation profile that resembles granulocyte-macrophage colony-stimulating factor (GM-CSF)-differentiated macrophages and the response to MTX is only observed in thymidylate synthase GM-CSF-dependent macrophages. To determine the molecular basis for the MTX anti-inflammatory action, we explored toll-like receptor (TLR), RA synovial fluid (RASF) and tumour necrosis factor receptor (TNFR)-initiated signalling in MTX-exposed GM-CSF-primed macrophages.

Polarization of the innate immune response by prostaglandin E2: a puzzle of receptors and signals.

Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E2 is the most abundant eicosanoid in the inflammatory milieu due to the robust production elicited by pathogen-associated molecular patterns on cells of the innate immune system. The different functions and cell distribution of E prostanoid receptors explain the difficulty encountered thus far to delineate the actual role of PGE2 in the immune response.

Sirtuin 1 is a key regulator of the interleukin-12 p70/interleukin-23 balance in human dendritic cells.

Stimulation of human dendritic cells with the fungal surrogate zymosan produces IL-23 and a low amount of IL-12 p70. Trans-repression of il12a transcription, which encodes IL-12 p35 chain, by proteins of the Notch family and lysine deacetylation reactions have been reported as the underlying mechanisms, but a number of questions remain to be addressed. Zymosan produced the location of sirtuin 1 (SIRT1) to the nucleus, enhanced its association with the il12a promoter, increased the nuclear concentration of the SIRT1 co-substrate NAD(+), and decreased chromatin accessibility in the nucleosome-1 of il12a, which contains a κB-site.

Apoptotic cells enhance IL-10 and reduce IL-23 production in human dendritic cells treated with zymosan.

Contact of apoptotic cells (AC) with phagocytes tilts the balance of pro-inflammatory and anti-inflammatory cytokines. To address the cell- and stimulus-dependency of this mechanism, human monocyte-derived dendritic cells were treated with Jurkat AC in the presence and absence of different stimuli. AC reduced the production of IL-23 and enhanced the production of IL-10 elicited by zymosan, but they did not influence IL-12 p70 production nor did they modify the effect of LPS.

Notch- and transducin-like enhancer of split (TLE)-dependent histone deacetylation explain interleukin 12 (IL-12) p70 inhibition by zymosan.

The fungal analog zymosan induces IL-23 and low amounts of IL-12 p70. This study addresses the molecular mechanisms underlying this cytokine pattern in human monocyte-derived dendritic cells. The transcriptional regulation of il23a, one of the chains of IL-23, depended on the activation of c-Rel and histone H3 phosphorylation, as judged from the association of c-Rel with the il23a promoter and the correlation between IL-23 production and Ser-10-histone H3 phosphorylation.

Eicosanoids in the innate immune response: TLR and non-TLR routes.

The variable array of pattern receptor expression in different cells of the innate immune system explains the induction of distinct patterns of arachidonic acid (AA) metabolism. Peptidoglycan and mannan were strong stimuli in neutrophils, whereas the fungal extract zymosan was the most potent stimulus in monocyte-derived dendritic cells since it induced the production of PGE(2), PGD(2), and several cytokines including a robust IL-10 response. Zymosan activated kappaB-binding activity, but inhibition of NF-kappaB was associated with enhanced IL-10 production.

The induction of IL-10 by zymosan in dendritic cells depends on CREB activation by the coactivators CREB-binding protein and TORC2 and autocrine PGE2.

Stimulation of human monocyte-derived dendritic cells with the yeast extract zymosan is characterized by a predominant production of IL-10 and a strong induction of cyclooxygenase-2, but the molecular mechanisms underlying this response are only partially understood. To address this issue, the activation of transcription factors that may bind to the il10 proximal promoter was studied. Binding activity to Sp1, Sp3, NF-Y, and cAMP response element (CRE) sites was detected in the nuclear extracts of dendritic cells; however these binding activities were not influenced by zymosan.

Cyclooxygenase-2 induced by zymosan in human monocyte-derived dendritic cells shows high stability, and its expression is enhanced by atorvastatin.

Cyclooxygenase (COX)-2 is a central enzyme of arachidonic acid metabolism, and its modulation by statins may explain some of the myocardial protective effects of these drugs. Dendritic cells (DCs) play a central role in microbial defense and in atherogenesis, and COX-2 expression in DCs is important for their migration to lymph nodes and antibody response, thus explaining why prostaglandin E(2) is a main component of the cocktails used to prepare DCs for clinical applications. On this basis, we addressed the effect of atorvastatin (ATV) on the release of arachidonic acid and on the expression of COX-2 in human monocyte-derived DCs.